Gene: {{page_name}}

Table of Contents

The pattern of mutations in KMT2C does not support its role in DLBCL

Overview

This gene has been reported to be recurrently mutated in DLBCL. The rate of mutations in KMT2C (MLL3) varies across published cohorts. In the initial study describing these mutations, it was suggested to be mutated in >15% of DLBCLs.¹ The actual rate of mutations may be much lower,² potentially due to the existence of germline variants in some studies.³ A more recent study suggested KMT2C mutations were more common in DLBCLs in patients of African ancestry.⁴ Although KMT2C mutations have been described as a feature of MCL in a single study, this pattern was not reproduced in other cohorts.⁵ Selective pressure analysis did not identify this gene as significantly enriched for either missense or truncating mutations, indicating that many, if not all, of the mutations in DLBCL may represent passengers.

Relevance tier by entity

Entity	Tier	Description
	2	Role of KMT2C mutations in BL requires confirmation
	1	High-confidence DLBCL gene
	2	Role of KMT2C mutations in MCL requires confirmation
	1	High-confidence PMBL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	65	0.0597	[0.0456,0.0738]
DLBCL	GAMBL with Reddy	2,088	138	0.0661	[0.0554,0.0767]
DLBCL	BC	231	6	0.0260	[0.0055,0.0465]
DLBCL	Dana-Farber	303	16	0.0528	[0.0276,0.078]
DLBCL	NCI	470	39	0.0830	[0.058,0.1079]
DLBCL	Reddy	999	73	0.0731	[0.0569,0.0892]
DLBCL	DLBCL_ICGC	85	4	0.0471	[0.002,0.0921]

FL

pathology	Collection	N	mutated	Incidence	CI
FL	GAMBL without Crouch	642	13	0.0202	[0.0094,0.0311]
FL	GAMBL with Crouch	1,189	48	0.0404	[0.0292,0.0516]
FL	BC	379	9	0.0237	[0.0084,0.0391]
FL	Kalmbach	164	3	0.0183	[0,0.0388]
FL	Crouch	547	35	0.0640	[0.0435,0.0845]
FL	FL_ICGC	99	1	0.0101	[0,0.0298]

BL

pathology	Collection	N	mutated	Incidence	CI
BL	GAMBL without Panea	309	6	0.0175	[0.0029,0.0321]
BL	GAMBL without ICGC/Zhou	320	22	0.0328	[0.0137,0.0519]
BL	GAMBL with Panea	410	23	0.0233	[0.009,0.0376]
BL	BLGSP	219	5	0.0228	[0.003,0.0426]
BL	Zhou/ICGC	90	1	0.0111	[0,0.0328]
BL	Panea	101	17	0.1683	[0.0953,0.2413]

MCL

pathology	Collection	N	mutated	Incidence	CI
MCL	GAMBL	160	1	0.0037	[0,0.0131]
MCL	BC_MCL	103	1	0.0097	[0,0.0286]
MCL	Barcelona	57	0	0.0018	[0,0.0126]

Mutation pattern and selective pressure estimates

Entity	Missense dN/dS	Nonsense dN/dS	Q value
BL	0.5410	0.0000	1.0000
FL	0.8804	0.0000	1.0000
DLBCL	1.0823	1.1361	0.9986

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2013-01-01 : Zhang : DLBCL 2014-05-08 : Zhang : MCL 2017-10-10 : Reddy : DLBCL 2019-07-23 : Zhou : BL 2021-04-01 : Sarkozy : PMBL

References

Sarkozy C, Hung SS, Chavez EA, Duns G, Takata K, Chong LC, Aoki T, Jiang A, Miyata-Takata T, Telenius A, Slack GW, Molina TJ, Ben-Neriah S, Farinha P, Dartigues P, Damotte D, Mottok A, Salles GA, Casasnovas RO, Savage KJ, Laurent C, Scott DW, Traverse-Glehen A, Steidl C. Mutational landscape of gray zone lymphoma. Blood. 2021 Apr 1;137(13):1765–1776.

Zhou P, Blain AE, Newman AM, Zaka M, Chagaluka G, Adlar FR, Offor UT, Broadbent C, Chaytor L, Whitehead A, Hall A, O’Connor H, Van Noorden S, Lampert I, Bailey S, Molyneux E, Bacon CM, Bomken S, Rand V. Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif. Blood Adv. 2019 Jul 23;3(14):2118–2127. PMCID: PMC6650741

Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, Choi W, Au WY, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers C, Naresh K, Evens A, Gordon LI, Czader M, Gill JI, Hsi ED, Liu Q, Fan A, Walsh K, Jima D, Smith LL, Johnson AJ, Byrd JC, Luftig MA, Ni T, Zhu J, Chadburn A, Levy S, Dunson D, Dave SS. Genetic heterogeneity of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:1398–1403. PMCID: PMC3557051

Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct;171(2):481–494.e15. PMCID: PMC5659841

Zhang J, Jima D, Moffitt AB, Liu Q, Czader M, Hsi ED, Fedoriw Y, Dunphy CH, Richards KL, Gill JI, Sun Z, Love C, Scotland P, Lock E, Levy S, Hsu DS, Dunson D, Dave SS. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014 May 8;123(19):2988–2996.